GME Research Review

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, Associate Professor of Psychiatry at Thomas Jefferson University, who selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by Dr. Mago.

73 patients with “treatment-resistant” bipolar I or II depression were included

Patients were currently at least moderately depressed

Here’s what I don’t like: the definition of treatment-resistant was “lack of response to two trials (lifetime) with antidepressants and/or mood stabilizers with documented efficacy in bipolar depression (lithium, lamotrigine, quetiapine, or olanzapine) in adequate doses for at least 6 weeks or until cessation of treatment due to side effects.” That doesn’t seem adequate to show treatment-resistance in the current episode. But anyway, let’s continue…

Patients with rapid cycling or high suicide risk were excluded. (This is important to know so that we don’t assume that the study can be generalized to these patients.)

The patients were randomized to receive either ECT or algorithm-based pharmacological treatment

ECT was done as follows: three sessions per week for up to 6 weeks, brief pulse stimulation, and right unilateral placement of electrodes. It should be noted that right unilateral placement of electrodes may be less effective than bilateral placement

The algorithm-based pharmacological treatment was based on the book by Goodwin and Jamison (Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd ed., 2007)

Now, this was not a double-blind trial. Both the patient and the investigators knew which treatment the patient was getting. To compensate for this potential source of bias, the rating scale interviews at Baseline and Week 6 (the most important times) were audiotaped and were scored by blinded raters

Results

ECT was statistically significantly more effective than algorithm-based pharmacological treatment for reducing severity of depression

From previous issues of GME Research Review, you may know that I recommend that you immediately ask what percentage of the subjects were improved, i.e., the response rate

The response rate was 74% for patients who received ECT versus 35% for patients who received pharmacological treatment. That is a BIG difference.

This study is a good step forward. Most importantly, it reminds us that we should keep ECT in mind as a potential option for patients with bipolar depression who have not responded to medication.

However, the study does have some limitations (small sample size, inclusion of both bipolar I and II, lack of blinding, limited standardization of treatment in the control group, etc). I hope that more clinical trials of ECT for bipolar depression are conducted soon.

Since patients with rapid cycling were excluded, the findings cannot be generalized to them. This is important because patients with rapid cycling are more likely to be treatment resistant.

As noted above, these patients may not be considered “treatment-resistant” for the current episode.

Letters to the Editor that followed publication of this article noted that response/remission rates could have been even better if bilateral ECT had been used. I think that at least in those patients who had a limited response to right unilateral ECT, it would have been appropriate to switch to bilateral ECT

A common diagnostic challenge is to differentiate between bipolar disorder and the hyperactivity, impulsivity, unstable mood, and sometimes-reckless behavior of a person with attention deficit hyperactivity disorder (ADHD).

However, it is very important to realize that a substantial minority of patients may have both ADHD and bipolar disorder

When younger patients present with major depression, it would be extremely useful to know which patients are more likely to turn out to have bipolar disorder

Background

Previous studies have found that ADHD in childhood and adolescence is associated with an increased risk of major depression and bipolar disorder in later life

Methods

This study used the Taiwan National Health Insurance Research Database

About 58,000 subjects < 30 years of age who had major depression with (n ~ 1,200) or without (n ~ 57,000) history of ADHD comorbidity were enrolled

Subjects who developed bipolar disorder during the next few years were identified

Results

Adolescents and young adults who had major depression with ADHD had a statistically significantly greater incidence of subsequent bipolar disorder compared to those with major depression but no ADHD (about 19% versus about 11%)

Even after statistically controlling for demographics and co-morbidities other than ADHD, presence of ADHD remained an independent risk factor for subsequent diagnosis of bipolar disorder

Conclusions

Patients with comorbid diagnoses of major depression and ADHD had an increased risk of diagnostic conversion to bipolar disorder compared to those who had major depression alone

Clinical Commentary

About 15% of patients with bipolar disorder (especially males) have a history of ADHD prior to first episode of bipolar disorder. That is well established

This study confirms the findings of a previous small study (Biederman et al., 2009)

A very important clinical implication of this study is that if a patient with ADHD has a major depressive episode, we must keep in mind that there is a greater chance that this will turn out to be bipolar disorder.

Emergence of subsequent bipolar disorder in 19% may not seem to be a huge proportion, but keep in mind that this is the percentage in only a few years of follow up. I assume that if these patients are followed up for several decades, a greater percentage may turn out to have bipolar disorder

Quite a few patients are unable to tolerate an SSRI in the first few weeks

If we could do something to improve the tolerability of SSRIs in the first few weeks, this could have a significant effect on improving the outcome of patients with major depressive disorder

Can such a simple thing as titrating the dose up have such a beneficial effect?

Background

Elderly patients may be more sensitive to side effects of paroxetine

These authors previously published a paper comparing slow versus standard titration of paroxetine in elderly patients

Slow titration: paroxetine was started at 2.5 mg/day and increased by 2.5 mg on alternate days to 10 mg/day

Standard titration: paroxetine was started at 10 mg/day

In both cases, the dose could be increased beyond 10 mg/day as clinically indicated

This paper extends their data to outcomes after 6 months of treatment

Methods

47 subjects from the original sample with a diagnosis of major depressive disorder and/or generalized anxiety disorder and >60 years of age were included

Results

At the end of 6 months, patients in whom paroxetine was slowly up-titrated were statistically significantly more likely to remit (84.0% vs. 54.5%; a big difference) and had lower depression and psychic anxiety levels

Dropout rate was 20% in the slow titration group compared with 77% in the standard titration arm. What a big difference!

However, there was an interesting twist in these findings: these differences were found ONLY in patients with generalized anxiety disorder

Conclusions

Paroxetine should be started at lower doses slowly titrated up in older depressed patients with more anxiety or generalized anxiety disorder

This is expected to reduce dropouts and improve outcomes

Clinical Commentary

This study shows that at least in elderly patients with significant anxiety, titrating the SSRI up slowly can have a huge impact on reducing dropouts

In my personal opinion as a clinician, we should ALWAYS titrate the SSRI up. The question in my mind is only how low to start and how slowly to go up

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